The proposed studies test the hypothesis that a specific T cell subset responding to Plasmodium yoelii mediates immune responses that downregulate protective immunity and are of no benefit to the host. Consistent with this hypothesis, a pair of congenic mice, BALB/c and BALB.D2.mls/a, have been identified which differ significantly in their ability to resist infection by P. yoelii. BALB.D2.mls/a mice have a BALB/c genetic background but are congenic for the endogenous mouse mammary tumor virus mtv-7. The superantigen encoded by mtv-7 deletes T cells which express T cell receptor chains Vbeta6, 7, 8.1 or 9. When infected with P yoelii, BALB/c mice develop anemia and a significant degree of peripheral parasitemia (up to 60%), and sometimes die of their infection. BALB.D2.mls/a become less anemic, and have a lower peripheral parasitemia (less than 30%) which resolves more quickly. These mice do not die from their infection. Thus the presence of Vbeta6, 7, 8.1 and/or 9 T cells in BALB/c mice correlates with increased susceptibility to disease. We hypothesize that these T cells could be deleterious to the host in two ways; 1) They could preferentially secrete cytokines which inhibit the development of protective immunity, 2) They could mediate the destruction of red blood cell precursors through specific autoimmune responses or through the production of cytokines which inhibit red blood cell generation. In the experiments proposed we will confirm and extend the observation that Vbeta-bearing T cells are deleterious to the host using adoptive transfer and in vivo depletion studies. We will then test the above hypotheses by analyzing cytokine production and the generation of autoimmune responses by these T cells.